Pleiotropic effects of the acute and chronic inhibition of the renin-angiotensin system in hypertensives.

Renin-angiotensin system (RAS) inhibition may exert beneficiary pleiotropic effects on heart hemodynamics in hypertensive patients. We aimed to assess these effects on coronary flow reserve (CFR) and left ventricular (LV) filling pressure after acute and long-term treatment. Thirty-nine patients (48.4±6.8 years) with newly diagnosed, never-treated essential arterial hypertension were consecutively recruited from an outpatient hypertension clinic. CFR in the left anterior descending artery and the ratio of mitral inflow E wave to the averaged mitral annulus tissue velocity of the E waves (E/e' ratio), as an estimate of LV filling pressure, were assessed by Doppler echocardiography. In the acute phase of the study, consecutive eligible patients were assigned to receive po Quinapril (Q) 20 mg (n=15) or Losartan (L) 100 mg (n=14) or no treatment (n=10) and were reexamined 2 h post treatment. In the chronic phase of the study, the patients were reevaluated after 1 month on the assigned treatment. During the acute phase, CFR (P=0.005) was significantly improved in the RAS inhibition as compared with the control group, independently of blood pressure (BP) changes. The E/e' ratio was also marginally improved (P=0.053), but this effect was more pronounced in patients with E/e' ratio>8 (P=0.005). CFR and E/e' ratio were also improved after 1 month of treatment, particularly in responders after the acute phase. In hypertensive patients, RAS inhibition acutely improved CFR and E/e' ratio independently of BP changes. An acute positive response in these parameters was closely related to sustained improvement after 1 month of single-drug treatment.

Inhibition of neurite outgrowth in N2a cells by leptophos and carbaryl: effects on neurofilament heavy chain, GAP-43 and HSP-70.

The neurodegenerative properties of the organophosphate ester leptophos (LEP) and the carbamate ester carbaryl (CB), both of which can cause neuropathic effects in animals, were investigated in differentiating mouse N2a neuroblastoma cells. At a sublethal concentration of 3 microM, both LEP and CB were able to inhibit the outgrowth of axon-like processes from N2a cells after only 4 h of exposure. Extracts of cells exposed to LEP showed decreased cross-reactivities with monoclonal antibodies that recognise the neurofilament heavy chain (NFH) and the growth-associated protein GAP-43. However, they exhibited increased cross-reactivity with a monoclonal antibody that recognises the heat shock protein HSP-70. In contrast, no changes were noted in the levels of antibody binding in blots of extracts of cells exposed to CB. It is concluded that, although both LEP and CB inhibit the formation of axons in vitro, the early biochemical changes underlying the neurodegenerative effects of the two compounds are different.

The toxicity of chlorpyrifos towards differentiating mouse N2a neuroblastoma cells.

The aim of this work was to study the effects of chlorpyrifos (CPF) on the outgrowth of axons by differentiating mouse N2a neuroblastoma cells. This was achieved by morphological, Western blotting and enzymatic analyses of cells induced to differentiate in the presence and absence of CPF added either at the same time (co-differentiation) or 16 h after (post-differentiation) the induction of cell differentiation. The outgrowth of axon-like processes was impaired following 4 or 8 h exposure to CPF in both co- and post-differentiation experiments. Western blotting analysis revealed reduced levels of neurofilament heavy chain (NF-H) following 8 h of exposure but no significant effect at 4 h under both co- and post-differentiation conditions. By contrast, levels of the heat shock protein HSP-70 were raised at both time points, but only in co-differentiation experiments. Neuropathy target esterase (NTE) activity was lower than controls following 4 or 8 h of exposure under co-differentiation conditions, but not under any post-differentiation conditions. The results suggest that the inhibition of axon production and maintenance by CPF in differentiating N2a cells may involve multiple targets, which are different under co- and post-differentiation conditions.

The transplacental effect of lead compounds on inorganic pyrophosphatase in brain, liver and kidneys of newborn rats.

The transplacental effect of tetraethyl lead or lead acetate on the activity of inorganic pyrophosphatase in brain, liver and kidneys of newborn rats varied with the organ, the lead compound, the dose, and the route and time of administration. Enzyme activity was usually decreased in brain and liver, suggesting adverse effects of lead on metabolism in these organs. The inorganic pyrophosphatase activity was generally increased in kidneys.

Effect of age on the seminal plasma and spermatozoa lead concentrations of bulls.

Blood, seminal plasma and spermatozoa lead concentrations were determined in Holstein (29 animals), Brown Swiss (14 animals) and Charoleux (11 animals) bulls aged 1-8 y. Blood concentrations were (mean +/- SD) 21.47 +/- 5.85, 18.71 +/- 6.60 and 23.27 +/- 6.75 ng Pb/ml respectively/each breed. Seminal plasma concentrations were 17.15 +/- 10.37, 13.62 +/- 10.10 and 14.03 +/- 11.31 ng Pb/ml, respectively. Spermatozoa concentrations averaged 74.93 +/- 48.10, 76.60 +/- 33.95 and 63.39 +/- 25.83 ng Pb/10(9) cells respectively. Age appeared to influence seminal plasma and spermatozoa lead levels, gradually decreasing in concentrations as the animals advanced in age.

Transplacental effect of lead compounds on tissue plasminogen activator activity, plasminogen activator inhibition and plasmin inhibition.

The transplacental effect of lead compounds (lead acetate and tetraethyl lead) on the tissue plasminogen activator activity (PAA), plasminogen activator inhibition (PAI) and plasmin inhibition (PI) was studied in the rat. The concentration of lead in organs of the newborn showed a great variation; the distribution of lead in the organs studied depended on the dose and the stage of gestation at injection. In each organ the concentration of lead was dose-dependent. In control specimens no lead could be detected. The tissue response of PAA, PAI and PI to the lead compounds also showed a great variation; however, there was no correlation between lead concentrations and PAA, PAI or PI responses. Changes of one or more of the parameters studied (PAA, PAI or PI) were noticed in lungs, liver, heart, brain and kidneys. The PAA was due to the tissue type plasminogen activator in all organs studied; in kidneys and lungs the urokinase type of plasminogen activator was also detected. Therefore, fetal tissue PAA, PAI and PI can be affected transplacentally by lead compounds.

Demonstration of plasminogen activator activity in the intima and media of the normal human aorta and other large arteries: immunological identification of the plasminogen activator(s).

The plasminogen activator activity (PAA) in extracts of the intima, media, and adventitia of the normal human aorta and other large arteries (carotid artery, renal artery and iliac artery) was studied with a sensitive, quantitative spectrophotometric assay using plasminogen and the chromogenic plasmin substrate S-2251. All layers of the arteries showed PAA which was highest in the adventitia, lowest in the media, while in the intima (aorta) PAA was intermediate, but much closer to that of the media. Plasminogen activator inhibition (PAI) was at the same level in all layers of the arteries studied. Plasmin inhibition (PI) was higher in adventitia than in intima (aorta), while in media the PI was intermediate. The PAA was due to the tissue-type plasminogen activator (t-PA), but not to the urokinase-type (u-PA), as judged by addition of respective antibodies. The relatively low PAA found in the intima of large arteries is therefore due to a low plasminogen activator and not a high plasminogen activator inhibitor activity or plasmin inhibitor level.